Drug Design, Development and Therapy
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Denosumab in the treatment of glucocorticoid-
induced osteoporosis: a systematic review and
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meta-analysis
Zeina A Yanbeiy
Karen E Hansen
Rheumatology Division, Department of
Medicine, University of Wisconsin School
For personal use only.
of Medicine & Public Health, Madison,
WI, USA
Correspondence: Karen E Hansen
Rheumatology Division, Department of
Medicine, University of Wisconsin School
of Medicine & Public Health, Room 4124
MFCB, 1685 Highland Avenue, Madison,
WI 53717, USA
Tel +1 608 263 3457
Fax +1 608 263 7353
Email keh@medicine.wisc.edu
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http://doi.org/10.2147/DDDT.S148654
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REVIEW
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
Objective: Glucocorticoid-induced osteoporosis (GIOP) is the most common form of
secondary osteoporosis. In May 2018, denosumab was approved for the treatment of GIOP
in men and women at high risk of fracture. We undertook a systematic review and meta-
analysis to summarize the efficacy and safety of denosumab in the prevention and treatment
of GIOP.
Methods: We searched PubMed, CINAHL, American College of Rheumatology and
American Society for Bone and Mineral Research meeting abstracts for relevant studies.
We included studies in which subjects were taking systemic glucocorticoid therapy and were
assigned to take denosumab or control therapy, and assessed the effect of treatment on areal
bone mineral density (BMD), fractures and/or safety.
Results: Three eligible studies were included in the primary meta-analysis. Denosumab
significantly increased lumbar spine BMD (2.32%, 95% CI 1.73%, 2.91%, P<0.0001) and
hip BMD (1.52%, 95% CI 1.1%,1.94%, P<0.0001) compared to bisphosphonates. Adverse
events, serious adverse events and fractures were similar between denosumab and bispho-
sphonate arms.
Conclusion: Results suggest that denosumab is superior to bisphosphonates in its effects on
lumbar spine and total hip BMD in patients with GIOP. There was no difference in the
incidence of infections, adverse events or serious adverse events. Studies were underpowered
to detect differences in the risk of fracture. Denosumab is a reasonable option for treatment
of GIOP. However, further studies are needed to guide transitions off denosumab.
Keywords: denosumab, glucocorticoid-induced osteoporosis, bone mineral density,
fractures, safety
Plain language summary
The collective data from three clinical trials shows that one year of denosumab therapy
increased spine and hip bone mineral density more than bisphosphonate therapy. The
collective data from the completed trials showed no difference in the risk of infections,
mild or serious side effects between people who took denosumab, compared to people who
took bisphosphonate therapy.
Introduction
Clinicians frequently prescribe glucocorticoids to treat common medical conditions
including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis,
polymyalgia rheumatica, giant cell arteritis and inflammatory bowel disease. Over
Drug Design, Development and Therapy 2019:13 2843–2852 2843
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 Yanbeiy and Hansen
20 years, the use of long-term oral glucocorticoid therapy
increased in the UK by 34%, with nearly 1% of the
population taking long-term (≥3 months) glucocorticoid
therapy in 2008.1 In some geographic regions, use is
even more common. For example, 17% of the population
in France used oral glucocorticoids at least once in 2014.2
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While most use was short-term, nearly 2% of the popula-
tion filled ≥6 prescriptions per year.2
Glucocorticoid use is the most common cause of sec-
ondary osteoporosis, and the most common form of drug-
induced osteoporosis. The cellular mechanisms by which
glucocorticoids harm the skeleton are complex. Initially,
glucocorticoids increase expression of receptor-activator
nuclear kappa B ligand (RANKL), a cytokine that
increases osteoclast differentiation and activation.
Simultaneously, glucocorticoids reduce expression of the
RANKL decoy receptor, osteoprotegerin. In concert, these
actions increase osteoclastic bone resorption, primarily in
For personal use only.
the initial phase of glucocorticoid therapy.3 With long-term
use, the main effect of glucocorticoid therapy is reduced
bone formation, via increased osteoblast and osteocyte
apoptosis.4 Glucocorticoid therapy can also contribute to
osteoporosis pathogenesis by causing hypogonadotropic
hypogonadism, reduced intestinal calcium absorption and
hypercalciuria.5
Glucocorticoid therapy causes a rapid decline in areal
bone mineral density (BMD). In one study,6 rheumatoid
arthritis patients who took prednisone 10 mg daily for 12
weeks and then tapered off by the 20th week experienced
an 8% decline in spine BMD, with partial recovery of
BMD by week 44. Not surprisingly, up to 25% of patients
taking systemic glucocorticoid therapy will develop
fractures.7–10
Until recently, only four medications were Food and
Drug Administration (FDA)-approved to treat glucocorti-
coid-induced osteoporosis (GIOP): alendronate, risedro-
nate, zoledronate and teriparatide. In clinical trials, all
medications increased spine BMD. Placebo-controlled
trials documented fewer fractures with risedronate11,12
and alendronate.13,14 Zoledronate was compared to rise-
dronate in a double-blind-controlled trial15 1 year of either
medication was associated with low fracture rates in both
arms, and no significant difference between the two drugs.
Teriparatide was compared to alendronate in a clinical trial
lasting 36 months16 teriparatide was associated with
greater increments in BMD and fewer vertebral fractures.
Denosumab is a human monoclonal antibody against
RANKL that is FDA approved to reduce osteoporotic
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fractures in postmenopausal women at high risk of frac-
ture, as placebo-controlled clinical trials documented its
ability to reduce major osteoporotic fractures. Denosumab
is also FDA approved to increase BMD in men with
osteoporosis or men at high risk of fracture. In May
2018, the FDA approved the use of denosumab to treat
GIOP in adults.
In RANKL knock-in mice exposed to glucocorticoids,
denosumab-preserved spine and hip BMD while concur-
rently reducing osteoclastic bone resorption, compared to
control mice.17 The efficacy of denosumab in the murine
model of GIOP, coupled with its efficacy in treating
postmenopausal osteoporosis, prompted human studies
using denosumab to treat GIOP. The purpose of this
systematic review and meta-analysis is to summarize
published data describing the efficacy and safety of deno-
sumab in the treatment of GIOP in adults. We registered
our study with PROSPERO (registration number
CRD42019129233); no other systematic reviews focus-
ing on denosumab use for GIOP were found in the
PROSPERO database.
Materials and methods
We searched PubMed and CINAHL from January 1, 2000
to September 1, 2017 using the terms “denosumab,” “glu-
cocorticoid,” “osteoporosis,” “glucocorticoid induced
osteoporosis” and “safety.” Studies in any language were
included. Two authors independently reviewed the
abstracts of all publications to determine eligibility. We
also searched the titles of abstracts presented at the
American College of Rheumatology and American
Society for Bone and Mineral Research in 2013, 2014,
2015 and 2016 using search terms “denosumab” and “glu-
cocorticoid.” We searched Pubmed to determine whether
relevant abstracts presented at these meetings were subse-
quently published. If not published, we next contacted
authors via email to inquire on the date of anticipated
publication. We updated our literature search in February
2019.
Studies were included if they recruited subjects taking
systemic glucocorticoid therapy, used denosumab and a
control or placebo arm, and assessed the effect of treat-
ment on BMD, fractures and/or safety. We excluded
review articles, case reports and case series. Figure 1
summarizes the total number of articles identified and
reasons for exclusion.
Both authors independently extracted data from
included publications including the year of publication,
Drug Design, Development and Therapy 2019:13
 Dovepress
Articles identified through CINAHL and PubMed
09/01/2000 - 02/28/2019
(n=95)
Articles screened for eligibility
(n=95)
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Full text articles assessed for eligibility
(n=7)
Articles included in systematic review and meta-
analysis
(n=4)
Figure 1 Flow diagram of literature search and study inclusion.
number of subjects assigned to control and denosumab
For personal use only.
therapy, and study outcomes including changes in spine
and hip areal BMD, clinical and radiographic fractures and
side effects. Of note, two clinical trials supported by
Amgen Pharmaceuticals20,23 did not report data in the
format needed to perform a meta-analysis (mean and SD
for the change in BMD). Thus, the authors formally
requested, and received, the needed data for these two
clinical trials from the company.
Both authors independently rated the quality of each
included publication, using the Downs and Black quality
scale for intervention studies.18 One author prepared a
table summarizing details of the included studies.
Statistical analysis
All data were summarized using the mean and SD, then
entered in duplicate into an Excel file and analyzed using
R software version 3.1.2 and the package “meta.” We
compared the effect of denosumab versus control therapy
on BMD, using Forest plots and a random effect model.
We also compared the odds of fractures, infections,
adverse events and serious adverse events between deno-
sumab and control therapy, using a random effect model.
We viewed Funnel plots to evaluate publication bias and
used the I2 statistic to assess study heterogeneity, with
25%, 50%, and 75% indicating low, moderate, and high
heterogeneity.19 Our primary analyses focused on the three
trials comparing denosumab to bisphosphonate therapy.
We performed additional analyses by including a fourth
trial in which placebo was the control arm.
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Yanbeiy and Hansen
88 excluded
48 review
10 no control arm
10 no focus on glucocorticoid induced osteoporosis
6 case report
4 not randomized
4 retrospective
2 animal study
3 letter to the editor
1 no relevant clinical outcome
3 excluded
3 no control arm
Results
From our literature search, we identified 95 articles of
interest. After screening for eligibility based on the afore-
mentioned inclusion criteria, 88 articles were excluded
(Figure 1). We assessed the remaining 7 full-length articles
for eligibility. Of these, 3 publications were excluded due
to lack of a control or placebo arm, leaving 4 publications
for inclusion in the meta-analysis. Table 1 and the para-
graphs below summarize the main findings of these
studies.
Dore et al20 reported a subgroup analysis of a multi-
center, double-blind, placebo-controlled, randomized trial
comparing the effects of denosumab and placebo on struc-
tural damage in rheumatoid arthritis patients.20 The trial
was sponsored by Amgen Incorporated (Thousand Oaks,
CA, USA). The subgroup analysis focused on changes in
BMD among 90 participants taking a median prednisone
dose of 5 mg daily at baseline and 4 mg daily at the end of
the study. Participants’ mean age was 56 years, 62% were
women and their mean lumbar T score was −0.6.
Participants were randomized to denosumab 60 mg, 180
mg or matching placebo every 6 months for 12 months.
Herein, we report the results for the placebo and 60 mg
denosumab arms, since the 60 mg dose is FDA approved
for GIOP and for osteoporosis in postmenopausal women
and men. We also restricted our analysis to the subset of
subjects who were not taking concurrent denosumab with
bisphosphonate therapy. At 12 months, subjects rando-
mized to denosumab (n=21) experienced numerically
greater increases in lumbar spine BMD compared to
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 Yanbeiy and Hansen Dovepress

participants randomized to placebo (n=15) therapy (3.5

Denosumab increased BMD in patients taking

greater increases in spine BMD than those

±2.9% vs 0.4±3.7%). Likewise, the denosumab arm

Subjects who switched to denosumab had

Denosumab increased spine BMD greater

Denosumab increased spine BMD greater

Denosumab inhibited structural damage.

than risedronate in patients starting or

experienced numerically greater gains in total hip BMD

glucocorticoids or bisphosphonates.
(1.6±1.9% vs −1.2±2.6%). Authors did not provide P-

than alendronate at 12 months

values for this subset of subjects.

continuing bisphosphonates

continuing glucocorticoids.
Mok et al21 conducted a 12-month, parallel-group,
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open-label, randomized-controlled trial in a single center

Study outcome

in Hong Kong. Researchers recruited patients with GIOP

and compared the change in BMD between patients who
continued bisphosphonates and those who switched to
denosumab. Participants must have taken bisphosphonate
therapy for >2 years to be included in the study.
Change in lumbar spine

Change in lumbar spine

Change in lumbar spine

Participants were randomized to continue bisphosphonate
Change in structural
Primary endpoint

damage in patients

therapy or switch to denosumab subcutaneously every 6

with rheumatoid

treatment arms

treatment arms

treatment arms
BMD between

BMD between

BMD between months for 12 months. Researchers enrolled 42 women

with a mean age of 55±13 years, of whom 71% were
arthritis

postmenopausal. All participants had rheumatic diseases;

Table 1 Summary of studies included in the meta-analysis of denosumab to treat glucocorticoid-induced osteoporosis

systemic lupus erythematosus (76%) was the most com-

For personal use only.

denosumab 120 mg at 0 and 6 months x

Denosumab 60 mg at 0 and 6 months or

Denosumab 60 mg at 0 and 6 months or

denosumab 60 mg at 0 and 6 months x

mon condition. The mean prednisolone dose was 4±2 mg

Continue bisphosphonate or switch to

alendronate 35 mg once a week x 12

Study intervention and duration

daily. Alendronate was used in 79%, risedronate in 12%

months (12 month data reported)
risedronate 5 mg once daily x 24
Placebo or denosumab 60 mg or

and ibandronate in 10% of the group at baseline. At 12

months, subjects randomized to denosumab experienced a
greater gain in lumbar spine BMD compared to subjects
who continued bisphosphonates, after adjustment for mul-
tiple co-variates affecting BMD (3.39±4.02% vs 1.48
12 months

12 months

±1.79%, P=0.01). By contrast, the between-arm changes

months

in total hip and femoral neck BMD were not statistically

significant.
Iseri et al22 conducted a 12-month prospective, open-
12- month visit
691 completed
42 entered, 40

32 entered, 28
Sample size

795 entered,
completed

completed

label, randomized, controlled study in a single center in

Japan, comparing denosumab to alendronate in 32 patients
with GIOP and concomitant glomerular disease.
Participants’ mean age was 66 years; 43% were female
Single center, randomized, open-label study in

Single center, randomized, open-label study in

Multicenter, randomized, double-blind trial in

including 9 women past menopause, and 18% had a prior

patients with glomerular disease who had

patients taking ≥7.5 mg prednisone daily

placebo-controlled trial in patients with
Multicenter, randomized, double-blind,

fracture. 71% of participants were continuing prednisolone

glucocorticoid induced osteoporosis
patients taking bisphosphonates and

at a median dose of 5 mg daily for at least 3 months, while

the remainder were initiating prednisolone. Participants
prednisolone ≥2.5 mg daily

were randomized to denosumab 60 mg subcutaneous

every 6 months or alendronate 35 mg by mouth weekly
rheumatoid arthritis

Abbreviation: BMD, bone mineral density.

for 12 months. Participants randomized to denosumab

Study design

experienced a greater increase in lumbar spine BMD com-

pared to participants randomized to alendronate (+5.3
±3.7% vs +2.0±4.5%, P<0.05). By contrast, there were
no significant between-arm differences in femoral neck
Dore, 201020

or ultra-distal radius BMD.

Study, year

Mok, 201521

Saag, 201823
Iseri, 201822

Saag et al23 conducted a 24-month, double-blind clinical

trial comparing denosumab to risedronate in adults starting
or continuing glucocorticoid therapy; 795 participants were

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 Dovepress
enrolled across Europe, Latin America, Asia and North
America, including 505 individuals in the “glucocorticoid
continuing” and 290 individuals in the “glucocorticoid initi-
ating” group. Subjects must be taking >7.5 mg prednisone
daily to be eligible. Subjects’ mean age was 64 years, the
majority were female (70%) and White (88%) while just
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under half of subjects (47%) reported a prior osteoporotic
fracture. The primary reason for glucocorticoid treatment
was a rheumatologic disorder (77%). The mean prednisone
dose was ~14 mg daily and 45% of subjects took concomi-
tant immunosuppression, although only 4% were taking
biologic medications. Patients were randomly assigned to
24 months of denosumab 60 mg subcutaneously every 6
months and daily oral placebo, or risedronate 5 mg daily
and subcutaneous placebo every 6 months. Denosumab
treatment was associated with a significantly greater 12
months increase in spine BMD compared to risedronate in
both the glucocorticoid continuing (4.3±4.0% vs 2.3±4.5%;
For personal use only.
P<0.0001) and glucocorticoid initiating groups (3.7±4.0%
vs 0.9±3.9%; P<0.0001). Likewise, treatment with denosu-
mab was associated with a greater increase in total hip
BMD compared to risedronate in both the glucocorticoid
continuing (2.2±2.9% vs 0.6±3.1%; P<0.0001) and gluco-
corticoid initiating (1.7±2.7% vs 0.1±2.6%; P<0.0001)
groups.
In our meta-analysis, we focused on three studies21–23
comparing changes in BMD between participants randomized
to denosumab or bisphosphonates. In these studies, partici-
pants receiving denosumab had a greater increase in lumbar
spine BMD compared to those receiving bisphosphonates
(2.32%, 95% CI 1.73%, 2.91%, P<0.0001, Figure 2) with
low study heterogeneity (I2=0%). Likewise, participants
assigned to denosumab had greater increase in hip BMD
Denosumab Bisphosphonate
Study& Year Total Mean SD Total Mean SD
Mok2015 20 3.39 4.02 20 1.48 1.79
Iseri2018 14 5.30 3.74 14 2.00 4.49
Saag2018, GC Starting 118 3.70 4.00 126 0.90 3.90
Saag2018, GC continuing 209 4.30 4.00 210 2.30 4.50
361 370
Random effects
2=0%, τ2=0,
Heterogeneity:I P=0.58
Favours bisphosphonate
Figure 2 Percent change in spine bone mineral density (BMD) between subjects randomized to denosumab or bisphosphonate therapy.
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Yanbeiy and Hansen
compared to those assigned to bisphosphonates (1.52%, 95%
CI 1.1%, 1.94%, P<0.0001, Figure 3) with low study hetero-
geneity (I2 0%). Finally, in the two studies21,22 that measured
changes in femoral neck BMD, there was no difference
between subjects assigned to denosumab versus those
assigned to bisphosphonates (1.35%, 95% CI −1.59%,
4.30%, P=0.37, Figure 4) with moderate heterogeneity
between studies
2
(I 46%). We found no difference in fracture incidence
between participants randomized to denosumab or bispho-
sphonates (1.16%, 95% CI 0.68%, 1.98%, P=0.59, Figure 5)
with low heterogeneity among the 3 studies (I2 0%). Funnel
plots of these studies are included in the Supplementary mate-
rials (Figures S1–S4).
In clinical trials among postmenopausal women, deno-
sumab therapy was associated with a higher risk of
infection.24 Therefore, patients prescribed prednisone
with denosumab might experience substantially more
infections, compared to patients treated with prednisone
and bisphosphonates. Reassuringly, we found no signifi-
cant difference in the rate of infections between partici-
pants treated with denosumab or bisphosphonate therapy
(2.16%, 95% CI 0.38%, 12.34%, P=0.39, Figure 6).
However, we observed moderate heterogeneity among
the 3 studies (I2 66%, Figure S5).
Adverse events were similar among subjects assigned to
denosumab or bisphosphonate therapy (2.23%, 95% CI
0.70%, 7.08%, P=0.17, Figures S6 and S7) but study hetero-
geneity was high (I2 83%). Finally, rates of serious adverse
events were similar among subjects assigned to denosumab
and those assigned to bisphosphonate therapy (1.11%, 95%
CI 0.42%, 2.93%, P=0.83, Figures S8 and S9), with low
study heterogeneity (I2 18%).
Percent change in spine BMD
MD 95%-CI Weight
1.91 [-0.02; 3.84] 9.3%
3.30 [ 0.24; 6.36] 3.7%
2.80 [ 1.81; 3.79] 35.1%
2.00 [ 1.18; 2.82] 52.0%
2.32 [ 1.73; 2.91] 100.0%
-6 -4 -2 0 2 4 6
Favours denosumab
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 Yanbeiy and Hansen Dovepress

Denosumab Bisphosphonate Percent change in total hip bone mineral density

Study Total Mean SD Total Mean SD MD 95%-CI Weight

Mok 2015 20 1.38 2.683 20 0.8 2.24 0.58 [-0.95; 2.11] 7.5%
Saag, GC Starting 2018 115 1.70 2.700 125 0.1 2.60 1.60 [ 0.93; 2.27] 39.2%
Saag, GC continuing 2018 208 2.20 2.900 208 0.6 3.10 1.60 [ 1.02; 2.18] 53.2%
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343 353
Random effects 1.52 [ 1.10; 1.94] 100.0%
Heterogeneity:I2=0%, τ2=0, P=0.48
-2 -1 0 1 2

Favours bisphosphonate Favours denosumab

Figure 3 Percent change in total hip bone mineral density (BMD) between subjects randomized to denosumab versus bisphosphonate.

Denosumab Bisphosphonate Percent change in femoral neck BMD

Study Total Mean SD Total Mean SD MD 95%-CI Weight
For personal use only.

Mok 2015 20 -0.14 2.24 20 -0.57 2.24 0.43 [-0.96; 1.82] 72.6%
Iseri 2018 14 1.80 4.12 14 -2.00 7.86 3.80 [-0.85; 8.45] 27.4%

34 34
Random effects 1.35 [-1.59; 430] 100.0%
Heterogeneity:I2=46%, τ2=2.165, P=0.17
-5 0 5

Favours bisphosphonate Favours denosumab

Figure 4 Percent change in femoral bone mineral density (BMD) between subjects randomized to denosumab versus bisphosphonate.

Denosumab Bisphosphonate

Study Events Total Events Total Risk ratio RR 95%-CI Weight

Mok 2015 0 21 0 21 0.0%

Iseri 2018 1 14 0 14 3.00 [0.13; 67.72] 3.0%

Saag 2018 26 398 23 397 1.13 [0.65; 1.94] 97.0%

433 432
Random effects 1.16 [0.68; 1.98] 100.0%

Hetertogeneity:I2=0%, τ2=0, P=0.54

0.1 0.5 1 2 10
Favours denosumab Favours bisphosphonate

Figure 5 Relative risk of fractures by randomization to denosumab or bisphosphonate therapy.

We performed additional meta-analyses, including a compared to subjects assigned to bisphosphonate or pla-

fourth trial20 in which placebo was the control arm. cebo, with no significant difference in the rates of fracture,
Changes in lumbar spine and total hip BMD were signifi- infection, adverse events or serious adverse events
cantly higher among subjects assigned to denosumab between treatment arms (Figures S10–S21).

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Denosumab Bisphosphonate
Study Events Total Events Total
Mok 2015 7 21 1 21
Iseri 2018 0 14 0 14
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Saag 2018 17 394 15 384
429 419
Random effects
Heterogeneity:I2=66%, τ2=1.121, P=0.09
0.1
Relative risk of infection by treatment
Figure 6 Relative risk of infection by treatment assignment.
Downs and Black scores indicated that two studies
were of good quality, and two were of excellent quality
For personal use only.
(Table 2).
Discussion
We performed a systematic review and meta-analysis of 4
randomized-controlled trials evaluating the efficacy and
safety of denosumab for the prevention and/or treatment
of GIOP. Treatment with denosumab provided signifi-
cantly greater increments in lumbar spine and total hip
BMD, compared to bisphosphonate therapy or placebo.
In a recent meta-analysis excluding GIOP studies,24
denosumab likewise increased spine and hip BMD
greater than that observed with bisphosphonate therapy.
In our meta-analysis, there was no difference in fracture
incidence; however, the total number of reported frac-
tures across trials was low, and the studies were not
powered to detect fracture differences between treatment
groups. By contrast, in the recent meta-analysis exclud-
ing GIOP studies,24 denosumab was associated with sig-
nificantly fewer fractures at 24 months, when compared
to alendronate (risk ratio 0.51, 95% CI 0.27–0.97).
A previous meta-analysis of 11 studies using denosu-
mab to treat postmenopausal women with osteoporosis
indicated an increased risk of serious adverse events
related to infections.25 However, we did not detect a dif-
ference in the frequency of infections between denosumab
and control groups. Rates of adverse events and serious
adverse events were also similar between denosumab and
control groups. In summary, denosumab represents a rea-
sonable therapeutic choice for patients with GIOP.
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Yanbeiy and Hansen
Risk ratio RR 95%-CI Weight
7.00 [0.94; 52.04] 36.4%
0.0%
1.10 [0.56; 2.18] 63.6%
2.16 [0.38; 12.34] 100.0%
0.5 1 2 10
assignment
We acknowledge several limitations of our study. First,
there were few randomized-controlled trials that met our
criteria for inclusion in the meta-analysis, leading us to
include open-label study designs. Second, none of the
studies were powered to detect a difference in fracture
between denosumab and comparator arms. Third, all stu-
dies were short in duration (12 months); thus the long-term
efficacy and safety of denosumab for GIOP cannot be
addressed at this time.
Discontinuation of denosumab warrants caution.
Researchers have recently recognized that discontinuation
of denosumab can markedly increase bone resorption, lead-
ing to sizeable declines in spine and hip BMD.25 Moreover,
some individuals have sustained one or more painful com-
pression fractures after stopping denosumab.26,27 There is
an especially high risk of new compression fractures among
individuals with prior vertebral fractures.27 At this time, it
remains unclear whether to recommend long-term denosu-
mab or switch to an alternative agent. Ongoing trials in
postmenopausal osteoporosis will clarify the best “exit strat-
egy” from denosumab, and might inform transitions off
denosumab for patients with GIOP.
In conclusion, data from this systematic review and meta-
analysis indicate that denosumab is a reasonable drug to
prescribe, in the prevention and treatment of GIOP. Its use
is particularly relevant in patients who have contraindications
or side effects from bisphosphonates or anabolic therapy, or
when patient compliance must be ensured. The American
College of Rheumatology guidelines to prevent and treat
GIOP,29 suggest use of denosumab as 4th line therapy, after
oral bisphosphonates, intravenous bisphosphonates and
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Table 2 Downs and black quality score for randomized and non-randomized studies of health care interventions

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Dore 2010 Mok 2015 Iseri 2018 Saag 2018

Yes=1, no or unable to determine=0

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Reporting

1 Hypothesis or aims clearly described 1 1 1 1

2 Main outcomes in introduction or methods 1 1 1 1
3 Patient characteristics clearly described 1 1 1 1
4 Interventions clearly described 1 1 1 1
5 Are the distribution of confounders clearly described in both groups (0, 1, 2) 1 1 2 2

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6 Main findings clearly reported 1 1 1 1
7 Estimates of random variability given for main outcome(s) 0 1 1 1
8 All adverse events of intervention reported 1 1 1 1
9 Characteristics of subjects lost to follow up reported 0 1 1 1
10 Actual probability (P-values) reported for main outcomes (not <0.05 but P=0.035) 1 1 0 1

External validity

11 Participants were representative of the source population 1 1 1 1

12 Subjects prepared to participate represented source population (% declined described) 1 1 0 1
13 Location and delivery of study intervention represented that of source population 1 1 1 1

Internal validity – bias & confounding

14 Participants blinded to treatment 1 0 0 1

15 Blinded outcome assessment 0 1 1 1
16 Any data dreding clearly described 0 1 1 1
17 Analyses adjustedfor differing length of follow up 1 1 1 1
18 Appropriate statistical analysis used 1 1 1 1
19 Compliance with study intervention was reliable 0 0 0 1
20 Outcome measures were valid and reliable 1 1 1 1
21 All participants were recruited from same source population 1 1 1 1
22 All participants were recruited over same time frame 1 1 0 1
23 Participants were randomized 1 1 1 1
24 Treatment assignment concealed from subjects and investigators 1 0 0 1
25 Adequate adjustment for confounding 1 1 1 1
26 Losses to follow up accounted for 1 1 1 1

Power

27 Adequate power to detect a treatment effect at α level of 0.05 0 1 1 1

21 24 22 28

Drug Design, Development and Therapy 2019:13

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teriparatide. Based on our literature review and meta-analy-
sis, and concerns about skeletal health after discontinuation
of denosumab, its place as 4th line therapy for GIOP seems
reasonable.
Abbreviations
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 95.181.176.89 on 18-Oct-2019
BMD, bone mineral density; FDA, Food and Drug
Administration; GIOP, glucocorticoid-induced osteoporo-
sis; RANKL, receptor-activator nuclear kappa B ligand.
Author contributions
YZ and KEH contributed equally to the design of the study.
YZ performed the primary literature review, which was repli-
cated by KEH. Both authors performed data extraction and
entry. KEH performed statistical analysis. YZ and KEH con-
tributed equally to drafting of the manuscript and approval of
the final version. Both authors agree to be accountable for all
For personal use only.
aspects of the work including data accuracy.
Disclosure
The authors report no conflicts of interest in this work.
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